Paliperidone, I, is an orally active drug useful for the treating of schizophrenia. Its chemical name is (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and its chemical structure is depicted below:

Paliperidone was first disclosed in European patent application EP0368388. In said application Paliperidone is prepared as depicted in Scheme 1.

In the synthesis exemplified in said document it is used a benzyl protecting group in the hydroxyl of pyridine II. Protected pyridine II is reacted with the lactone III where the protecting group in the hydroxyl avoids selectivity problems during the coupling step. Then, the phosphoryl chloride substitutes the resulting hydroxyl group with chlorine and compound IV is obtained in a 62.3% yield, again the benzyl group avoids selectivity problems. Compound IV is then hydrogenated in the presence of a palladium catalyst to remove the benzyl protecting group and to reduce the pyridine ring. Compound V is obtained quantitatively.
Said compound V is coupled with compound VI in the presence of diisopropylamine in methanol to yield the desired compound I in a 21% yield.
International patent applications WO2008021345A and WO2008024415A also relate to the synthesis of Paliperidone and use a similar approach, also using, a benzyl protecting group with low to moderate yields.
The use of protecting groups is widely present in the field of organic synthesis, and they are useful to differentiate two or more moieties with similar reactivity. Even that, its use reduces the atomic economy of the reaction and increases the waste by-products. All this increases the costs and the environmental problems of the reaction.
Not only that, but in this case the use of the benzyl protecting group increases the amount of hydrogen gas, which is a toxic and flammable gas, consumed during the synthesis process.
There are documents describing the synthesis of suitable intermediates, such as EP0730594 and EP0808313 that prepare compound VIII in xylene and p-toluenesulphonic acid (Scheme 2). The resulting hydroxyethyl moiety is activated with a mesyl group.

In EP1791839 it is also described the synthesis of compound VIII in similar conditions and it is said that in the conditions described in EP0730594 and EP0808313 compound VIII is poorly soluble and that renders a difficulty in the following reactions (not described in the document). In EP1791839 this problem is solved using chlorobenzene.
In WO2008021345 it is described the preparation of Paliperidone, I, via the coupling of compounds V and VI using an inorganic base (Scheme 3).

Therefore, there is a need in the art to develop a new process to obtain Paliperidone with higher yield, increase atomic economy and less environmental drawbacks.
All the documents cited therein are enclosed in its entirety by reference.